Fetal Lung Development:Role of Wnt5a Signaling

描述（申请人提供）：通过无翅/卷曲通路的发育信号是一种进化上高度保守的机制，在许多器官的形态发生中起重要作用。关于这一途径及其介质在肺形态发生中的作用的信息很少。我们研究了Wnt5a功能性缺失对小鼠肺发育的影响。突变小鼠有多种发育异常，并在出生后不久死于呼吸功能不全。初步数据表明，缺乏Wnt5a会导致细胞增殖增加，假腺分支形态发生增强，肺/体大小比增加，但会抑制肺泡间隔（间质增厚）的成熟。此外，Shh、Ptc、Fgfl0和Bmp4在Wnt5a（-/-）肺中的表达均升高。我们建议：

DESCRIPTION (provided by applicant): Developmental signaling through the wingless/frizzled pathway is an evolutionarily highly conserved mechanism that figures importantly in morphogenesis of many organs. Little information is available regarding the role of this pathway and its mediators in lung morphogenesis. We have examined the consequences of functional deletion of Wnt5a on lung development in mouse. The mutant mice have multiple developmental abnormalities and die shortly after birth with respiratory insufficiency. Preliminary data suggest that absence of Wnt5a results in increased cellular proliferation, enhanced pseudoglandular branching morphogenesis, increased overall lung/body size ration, but inhibits the maturation of the alveolar septa (thickened interstitium). Also, expression of Shh, Ptc, Fgfl0 and Bmp4 are all increased in Wnt5a(-/-) lungs. We propose that: Hypothesis: WNT5a affects fetal lung development through interactions with the SHH pathway. Three Specific Aims are proposed to test the latter hypothesis. Specific Aim 1. To further investigate the role Wnt5a by generating & characterizing SpC: Wnt5a transgenic mice. Specific Aim 2. To determine the interactions of SHH & WNT signaling in lung development. Specific Aim 3. To determine receptor specificity and intracellular mediators of WNT5a pathway in the lung. Characterization of the precise role of Wnt5a will contribute to our understanding of cell-to-cell communication and lung development. This information will be of utility in understanding the molecular mechanisms of congenital and induced lung disease.